Hepatocellullar injury in hepatitis B virus (HBV) infection is believed to result from immune-mediated mechanisms related to host clearance of this noncytopathic virus. We have demonstrated that the immune response to the hepatitis B surface antigen (HBsAg) is regulated by immune response (Ir) genes that map to the murine MHC. High responder and nonresponder haplotypes have been identified. A correlation of HLA-DR phenotype and nonresponsiveness to the trial, HBsAg vaccine in human recipients has also been reported. We propose to comprehensively study the H-2 restricted, immune response to HBsAg in a murine model to evaluate: the influence of genetic and immunoregulatory factors, the cellular mechanisms and circumvention of genetic and induced HBsAg-nonresponsiveness, and definition of distinct epitopes on this complex antigen. Specific studies will include: (1) analysis of genetic mechanisms whereby the I-A and I-C subregions influence the immune response to distinct determinants on HBsAg; (2) the epitope specificity and I-region restriction of HBsAg-specific functional T cell subsets; (3) the use of chemically synthesized peptide analogues of HBsAg to study the nature of the antigenic epitopes recognized by T cell functional subsets and B cells; (4) examination of mechanisms of HBsAg nonresponsiveness and strategies to bypass it; and (5) analysis of the influence of HLA-linked genes on the human immune response to HBsAg immunization. In view of the extensive preliminary data, the availability of purified HBsAg preparations and synthetic peptide analogues, and the experience of the co-investigators in developing HBsAg-specific, serological and cellular assay systems, this model offers a unique opportunity to study the regulation of the immune response to HBsAg, a pathogenetically relevant, multideterminant, Ir-restricted antigen. This system is expected to provide critical information applicable to HBsAg vaccine strategies, the understanding of pathogenetic mechanisms in HBV infection as well as basic information relating to mechanisms of Ir gene function.